The most frequent route of HIV transmission occurs across mucosal tissues. Unfortunately, the earliest events in mucosal transmission are poorly defined. Two features of transmission stand out. First, mucosal transmission is inefficient. Second, in the majority of newly infected individuals the virus rapidly establishes infection in gut associated lymphoid compartments. We regard a comprehensive understanding of these two aspects of mucosal transmission as critically important information that can be utilized in the development of an effective HIV vaccine. HIV must overcome multiple structural barriers and only achieves productive infection upon gaining access to metabolically active CD4+ T cells. This process requires that the HIV envelope protein first binds to the CD4 receptor and subsequently to a co-receptor (CCR5 or CXCR4). However, the CD4 receptor is expressed at high levels not just on metabolically activated cells, but also on resting cells, which are a poor substrate for productive infection. We have identified the integrin &#945;4&#946;7 as an additional HIV receptor on the surface of CD4+ T cells. &#945;4&#946;7 is not an entry receptor, however, unlike CD4, integrin &#945;4-&#946;7 is preferentially expressed on a subset of cells in mucosal tissues that are activated. We are addressing the hypothesis that a direct interaction between gp120 and &#945;4&#946;7 expressing cells provides important advantages that facilitate transmission across mucosal surfaces. By engaging these cells, a virion is effectively targeting a subset of CD4+ T cells that is relatively more susceptible to infection. In the past year, using an SIV/macaque model we have shown that targeting these cells with and antibody to &#945;4&#946;7 reduces the efficiency of transmission in a significant way. We continue to pursue the goal of better understanding the specific molecular events surrounding mucosal transmission because we regard this as critical information that will allow us to identify new strategies to prevent HIV transmission.